JP2008530153A - Combinations in the treatment of manidipine and statins - Google Patents

Abstract

  (±) -1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 2- [4- (diphenylmethyl) -1-piperazinyl] ethyl methyl ester ( Manidipine) or a pharmaceutical comprising a physiologically acceptable salt and a statin or a physiologically acceptable salt.

Description

  The present invention relates to (±) -1,4-dihydro-2,6-dimethyl combined with statins or physiologically acceptable salts thereof for the treatment and / or prevention of cardiovascular diseases. 4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 2- [4- (diphenylmethyl) -1-piperazinyl] ethyl methyl ester (manidipine) or a physiologically acceptable salt thereof With respect to use, the disease includes atherosclerosis, combined hypertension and hyperlipidemia, coronary heart disease or coronary artery disease (CAD), angina, myocardial infarction (heart attack) and stroke.

  In a particular embodiment, the invention relates to a medicament comprising a defined combination of manidipine or a physiologically acceptable salt thereof and a statin or a physiologically acceptable salt thereof.

  In another aspect, the invention provides a pharmaceutical composition for oral administration comprising the determined combination, and a) a therapeutically effective amount of manidipine or its physiology in the first unit dosage form. A pharmaceutically acceptable salt and a pharmaceutically acceptable carrier or diluent, b) a therapeutically effective amount of a statin or a physiologically acceptable salt thereof and a pharmaceutically agent in a second unit dosage form It also relates to a kit comprising an acceptable carrier or diluent and c) container means for containing the first and second dosage forms.

BACKGROUND OF THE INVENTION A cardiovascular disease, disorder or event that affects the heart and / or related blood vessels is a major cause of morbidity and one of the most common causes of death.

  They are mostly caused by atherosclerosis, a series of changes composed of thickening and elastic loss of the arterial vessel wall.

  Hypertension and hyperlipidemia, especially hypercholesterolemia, have been considered to be major risk factors for the progression of atherosclerosis.

  In the last few years, newer risk factors for the progression of atherosclerosis have been identified and include inflammation and its markers such as C-reactive protein (CRP), oxidative stress and endothelial dysfunction.

  More recently, clinical, pathological and experimental observations strongly support a role for systemic inflammation in the pathogenesis of cardiovascular disease (Non-Patent Document 1).

  Endothelial dysfunction disrupts homeostasis of vasoactive substances. Vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and levels of angiotensin II, a vasoconstrictor that promotes proliferation and influx of cytokines, and endothelin, a vasoconstriction hormone The level of 1 (ET-1) increases.

  In hypertension, diseases and reductions in lipid metabolism, primarily expressed as increased plasminogen activator inhibitor type 1 (PAI-1) levels and decreased tissue plasminogen activator (t-PA) activity. A close relationship between fibrinolysis was also demonstrated.

  Recent hypertension treatment guidelines focus on the role of overall risk factor management and not only lower blood pressure but also lower levels of low density lipoprotein (LDL) cholesterol to improve overall cardiovascular risk characteristics States that to do.

  Drug therapy hypertension has recently been associated with angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), diuretics, β-blockers, and two main groups: dihydropyridines and non-dihydropyridine derivatives. , Based on the use of different drug species including calcium channel blockers-CCBs-(also referred to as calcium antagonists).

  Certain dihydropyridine calcium-channel blockers appear to have anti-atherosclerotic properties.

  Manidipine, ie, (±) -1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 2- [4- (diphenylmethyl) -1-piperazinyl] ethyl Methyl ester is a long-acting calcium channel blocker belonging to the dihydropyridine species. It was first disclosed in US Pat.

  Hypercholesterolemia is now treated with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, commonly referred to as statins.

  The statins currently on the market are lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, pitavastatin and rosuvastatin (rosuvastatin).

  Statins are known to reduce LDL-cholesterol levels.

  Furthermore, among several side effects of statins, it has been reported in the literature that they also have anti-inflammatory properties and their atheroprotective effects are not only due to lipid-lowering effects but also their anti-inflammatory effects. -It was suggested that the inflammatory properties also yield. In particular, certain statins improve endothelial function as reflected by reduced ICAM-1 and IL-6 levels (2).

  Recently, statins have reduced CRP levels in a way that is largely independent of LDL cholesterol levels, and the CRP levels resulting from statin therapy are clinically similar to those of LDL cholesterol levels obtained with the same therapy. It has been reported that they can have similarities (Non-Patent Document 3).

  On the other hand, contrasting data on the effects of dihydropyridine CCBs on CRP levels have been reported.

  Yasunari K et al. (Non-Patent Document 4) found that amlodipine did not significantly change CRP levels in hypertensive patients, whereas Takase H et al. (Non-patent Document 5) found nifedipine angina. It has been found that CRP levels are reduced after long-term treatment in the patient's coronary sinus.

Another advantageous aspect of the use of statins or certain dihydropyridine calcium-channel blockers is due to their ability to protect the myocardium from damage associated with cardiovascular events such as myocardial infarction or stroke.

  For example, simvastatin has been found to protect the ischemia-reperfusion myocardium in normal cholesterol rat hearts (Non-Patent Document 6), while Sakuraguchi et al. Benidipine) was shown to exhibit relative cardioprotection in an in vitro model of ischemia-reperfusion (isolated rat heart).

  In view of what has been reported above, an effective combination of antihypertensive agents and statins can act on risk factors for cardiovascular disease in an additional or synergistic manner and can also provide cardioprotective effects Would be very advantageous.

Prior Art Imai Y et al. (Non-Patent Document 8) investigated the effect of pravastatin on total cholesterol levels in patients with hypertension in addition to mild renal dysfunction and hyperlipidemia.

  In particular, parameters of blood pressure, serum total cholesterol, HDL cholesterol and triglycerides were measured.

  Patients were treated with dihydropyridine CCBs during the study and 6 of them took 16.0 ± 5.5 mg manidipine according to Table 2.

  A group of patients taking various dihydropyridines was not identified and the results obtained were reported together, independent of the type of treatment.

  The purpose of the study was to investigate whether pravastatin can lower serum total- and LDL-cholesterol levels in patients with mild renal dysfunction. The results show that pravastatin treatment reduces serum total cholesterol levels from 251.4 mg / dl to 218.2 mg / dl, and consequently less than that reported in the prior art for pravastatin alone (greater than 20%). 13%), indicating a reduction.

  Blood pressure did not change during the study.

  Jukema et al. (Non-Patent Document 9) refer to the Regression Growth Evaluation Study Study (REGRESS) to assess the effects of pravastatin on the progression of atherosclerosis in patients treated with CCBs. Handles post-mortem analysis of clinical trials.

  However, the REGRESS study is not designed to test the effects of CCB administration, and the author himself recognizes that no clear conclusion can be drawn regarding the beneficial effects of CCB addition on lipid-lowering therapy ( 429, 2nd column, lines 11-14). In addition, the author also noted that it is not known whether all CCBs or only some of these drugs could expand the anti-atherosclerotic effect of plusvastatin.

  Manidipine is not listed among the CCBs.

  In view of the possible beneficial effects on atherosclerosis, combinations of dihydropyridine calcium channel blockers and lipid lowering agents, particularly statins, have also been disclosed in the patent literature.

  Patent document 2 ('259) in the name of Pfizer describes pharmaceutical combinations of anthropine and atorvastatin and their pharmaceutically acceptable salts, kits containing such combinations, as well as angina pectoris, atherosclerosis Of the use of such combinations for treating patients suffering from complications, combined hypertension and hyperlipidemia and for treating patients presenting signs of cardiac risk.

  In this report, the anti-atherosclerotic, anti-anginal, anti-hypertensive and anti-lipemic effects of this combination are reported to be greater than the anti-anginal effects obtained by separately administering the two active ingredients. Has been. It has also been reported that the effect of this combination is to manage cardiac risk in mammals at risk of suffering from a malignant cardiac event, the effect of administering the two active ingredients separately Is greater than the sum of the cardiac risk management effects obtained.

  In the examples, the usefulness of the combination of the present invention is demonstrated by its activity in clinical formulations for the treatment of atherosclerosis, angina pectoris, hypertension and the management of cardiac risk.

  In particular, this combination has been found to be effective in delaying, stopping, or regressing the progression of existing cardiac arterial disease.

  Patent Document 3 ('260) and Patent Document 4 (' 263) describe a pharmaceutical combination of atorvastatin or a pharmaceutically acceptable salt thereof with an antihypertensive agent that is not an anthropine and a salt thereof, and an anlogin or a pharmaceutical thereof. Similar applications relating to pharmaceutical combinations of pharmaceutically acceptable acid addition salts with statins or their pharmaceutically acceptable salts.

  U.S. Pat. No. 5,849,095 in the name of Mason also relates to the combination of anlodipine with either atorvastatin or an atorvastatin metabolite. This combination exhibits a synergistic antioxidant effect on lipid peroxidation in membrane vesicles rich in human low density lipoprotein (LDL) and polyunsaturated fatty acids.

  More recently, Fograi et al. (10) reported serum tissue plasminogen activator (t-PA) and inhibitors in insulin resistant hypertensive hypercholesterolemia patients characterized by exacerbated fibrinolysis ( PAI-1) The effect of an anthropine-atorvastatin combination on activity was evaluated.

  The results suggest that the anthropine-atorvastatin combination improves fibrinolysis balance and lowers blood pressure over monotherapy in patients with hypertensive hypercholesterolemia with impaired insulin sensitivity.

  Patent document 6 in the name of Bayer treats cardiovascular disease, a combination of at least one dihydropyridine compound, such as nifedipine or lacidipine, preferably nifedipine, and an HMG-CoA reductase inhibitor, preferably cerivastatin. The use of this combination to make, the chemicals containing this combination and their manufacture.

  The inventors generally state that the combination of this invention can reduce the dose of the two active ingredients to show a synergistic antioxidant effect.

They also state that the combination of nifedipine and cerivastatin has been found effective in the treatment of hypertension, heart failure and other cardiovascular diseases. Only dispensing examples have been reported.

  Another combination between calcium-channel blockers and statins proposed in the literature comprises anlodipine and simvastatin, lacidipine and simvastatin, anlodipine and lovastatin, nifedipine and lovastatin, and felodipine and simvastatin.

  U.S. Patent No. 6,057,038 selects patients known to have higher than normal levels of markers of systemic inflammation and calcium-channel blockers, beta-adrenergic receptor blockers, cyclooxygenase-2 inhibitors, or It relates to a method of treating a patient comprising administering an agent selected from an angiotensin system inhibitor to reduce the risk of cardiovascular disease.

  Tests generally state that this method may further comprise other co-administered agents including lipid lowering agents.

Among the markers of systemic inflammation are CRP and the soluble cell adhesion molecule ICAM-1.
European Patent No. 94195 WO99 / 11259 pamphlet WO99 / 11260 pamphlet WO99 / 11263 pamphlet International Publication No. 00/64443 Pamphlet WO 01/21158 pamphlet International Publication No. 01/15744 Pamphlet Jain M et al Nat Rev Drug Discov 2005, 4 (12), 977-987 Nawawi H et al Atherosclerosis 2003, 169, 283-291 Ridker PM et al New Engl J Med 2005, 352, 20-28 Yasunari K et al J Am Coll Cardi 2004, 43, 2116-2123 Takase H et al, Am J Cardiol, May 2005, 95, 1235-1237 issued on-line on 9.07.2004. Allan M et al Circulation 1999, 100, 178-184 Sakaguchi et al, Circulation 2004, 68, 241-246 Imai Y et al, Clin Expert Hyper 1999, 21 (8), 1345-1355. Jukema et al issued on Arterioscler Thromb Vasc Biol. 1996 16 (3), 425-30 Fogari et al, J Hypertens 22 (Suppl 2) 2004, S365

  Several compositions comprising anti-hypertensive agents, and in particular dihydropyridine, in combination with lipid-lowering agents, and in particular statins, have been proposed in the prior art, but further for the prevention and treatment of cardiovascular diseases There remains a need for effective drugs.

The object of the present invention is (±) -1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 2- [4- (diphenylmethyl) -1 -Piperazinyl] ethyl methyl ester (manidipine) or a physiologically acceptable salt thereof and a drug comprising a statin or a physiologically acceptable salt thereof.

  The statin is advantageously selected from lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, pitavastatin and rosuvastatin.

  One preferred statin is simvastatin.

DESCRIPTION OF THE DRAWINGS The drawings show the time course of left ventricular end-diastolic blood pressure (LVEDP) in perfused rat heart specimens subjected to ischemia-reperfusion. Hearts were excised from rats treated orally with manidipine and simvastatin alone or in combination for 5 consecutive days. The bar graph shows the quantification of the area under the curve (AUC) for the LVEDP curve (right panel). Data are mean ± SEM of 8 hearts per group. ^* P ^<0.05 versus ^{control, ** P <0.01, *** P} <0.001;# P <0.01 relative to simvastatin alone.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to (±) -1,4-dihydro-2,6-, in combination with statins or physiologically acceptable salts thereof for the treatment and / or prevention of cardiovascular diseases. The use of dimethyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 2- [4- (diphenylmethyl) -1-piperazinyl] ethyl methyl ester (manidipine) or a physiologically acceptable salt thereof The disease includes atherosclerosis, combined hypertension and hyperlipidemia, coronary heart disease or coronary artery disease (CAD), angina, myocardial infarction (heart attack) and stroke.

  In a particular embodiment, the invention relates to a medicament comprising a fixed combination of manidipine or a physiologically acceptable salt thereof and a statin or a physiologically acceptable salt thereof.

  In another aspect, the present invention provides a) a therapeutically effective amount of manidipine or a physiologically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent in a first unit dosage form, b) A therapeutically effective amount of a statin or a physiologically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent in a second unit dosage form; and c) the first and second dosage forms. It also relates to a kit comprising container means for containing.

  In preliminary clinical trials, manidipine has actually been found to act in an additive and / or synergistic manner against multiple risk factors for atherosclerosis and inflammation in the combination of the present invention.

  Manidipine and statin combination administration significantly reduces both systolic and diastolic blood pressure (SBP and DBP) compared to manidipine alone and lowers total cholesterol levels.

  This is another advantage because this combination also improves fibrinolysis balance and worse fibrinolysis has been described as a risk factor for cardiovascular disease.

  Furthermore, the combination treatment also provides a synergistic effect on the reduction of ICAM-1 levels compared to each single drug.

  An additional effect also arises with respect to reduced CRP levels, another marker associated with inflammation and the risk of progression of cardiovascular disease.

  The reduction in markers of inflammation is particularly surprising and has not been previously disclosed for the combination between dihydropyridine calcium-channel blockers and statins.

  The cardioprotective effect of the inventive combination of manidipine and statin was also investigated.

  In studies conducted with isolated perfused rat hearts, administration of manidipine and simvastatin given orally over 5 consecutive days may cause significant suppression of ventricular dysfunction after ischemia It was found. The reduction in ventricular stiffness and recovery of myocardial contraction induced by the combination appears to be consistent with a synergistic type of pharmacodynamic interaction.

  With the findings disclosed in this application, manidipine in combination with statins is useful for therapies to effectively treat or prevent cardiovascular disease and from myocardial damage related to cardiovascular events such as myocardial infarction and stroke. It will be seen that it is useful for protecting.

  Manidipine or a physiologically acceptable salt thereof, and a statin or a physiologically acceptable salt thereof are determined separately or together, preferably together, in a fixed amount and a quantitative ratio. Can be administered as a combination.

  Manidipine is preferably used in the hydrochloride form.

  The dosage amount of manidipine in a given combination is between 5 and 30 mg. Preferably, the dosage of manidipine as the hydrochloride is between 10 and 20 mg.

  Advantageously, the statin is selected from lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, pitavastatin and rosuvastatin or a physiologically acceptable salt thereof, such as the sodium salt.

  One preferred statin is simvastatin.

  Other statins that can be used are rivastatin, mevastatin, fluindostatin, verostatin, dalvastatin, dihydrocompactin, and compactin.

The ratio that manidipine and statin can be used in the fixed combination of the invention is variable. Depending on the choice of statins, the dosages that can be used within the scope of the present invention will vary based on the respective therapeutic dosage ranges.

Advantageously, when a statin selected from simvastatin, pravastatin, fluvastatin and rosuvastatin is used, it is administered at the following dosage:
Simvastatin, generally 2.5 mg to 160 mg, and preferably 10 mg to 80 mg;
Pravastatin, generally 2.5 mg to 160 mg, and preferably 10 mg to 40 mg;
Fluvastatin, generally 2.5 mg to 160 mg, and preferably 20 mg to 80 mg;
And rosuvastatin, generally 2.5 mg to 160 mg, and preferably 10 mg to 80 mg.

  In one preferred fixed combination of the invention, a dosage of 10-20 mg of manidipine hydrochloride is combined with a dosage of simvastatin of 10-80 mg, preferably 40-80 mg.

  The combination according to the invention is advantageously administered in the form of a pharmaceutical composition for oral administration comprising a pharmaceutically acceptable carrier or diluent.

  Pharmaceutical compositions for oral administration can be advantageously administered in the form of tablets or capsules, preferably tablets.

  Alternatively, if the manidipine and statin are administered separately, the individual components can be formulated separately. In this case, the two individual components do not have to be taken at the same time, and in some cases, the intake at different times may be advantageous to obtain an optimal effect. In particular manidipine will be taken in the morning and statins will be taken in the evening. For such separate administration, the two individual component formulations, such as tablets or capsules, can be packaged simultaneously in a suitable container means. Such separate packaging of the components in suitable container means is also described as a kit.

  Accordingly, the present invention provides a) a therapeutically effective amount of manidipine or a physiologically acceptable salt and pharmaceutically acceptable carrier or diluent thereof in a first unit dosage form, b) a second Containing a therapeutically effective amount of a statin or a physiologically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent in a unit dosage form, and c) the first and second dosage forms It also relates to a kit comprising container means for.

  The combination of the present invention has a wide range of fields of action. It is primarily used for the treatment and prevention of cardiovascular diseases such as angina pectoris, atherosclerosis, combined hypertension and hyperlipidemia, coronary heart disease or coronary artery disease, myocardial infarction and stroke. However, it may also be useful in the treatment of other cardiovascular diseases including restenosis, transplant arterial disease, transient ischemic stroke, vascular thrombolysis, heart failure and cardiac arrest.

  The following examples illustrate the invention in more detail.

Example 1-Effect of manidipine and simvastatin, alone and in combination, in patients with hypertensive hypercholesterolemia The purpose of this study was to determine whether plasma tissue plasminogen activator (t- Was to evaluate the effect of manidipine-simvastatin combination on plasma intracellular adhesion molecule type-1 (ICAM-1) and on serum C-reactive protein (CRP) on PA) and inhibitor (PAI-1) activity .

  After the 4-week placebo final phase period, 30 patients with hypertensive hypercholesterolemia were randomly assigned manidipine 20 mg or simvastatin 40 mg or manidipine-simvastatin combination treatment according to the 3 × 3 crossover setting, each treatment for 12 weeks Had a period.

  Blood pressure was measured on the last phase of placebo and on the last day of each treatment period and venous blood samples were taken (at the same time in the morning) to measure plasma t-PA and PAI-1 activity, TC plasma, ICAM-1 and CRP. evaluated.

  The main results are shown in Table 1 below.

  As can be appreciated from the reported results, manidipine monotherapy was significantly effective in reducing both systolic and diastolic blood pressure (SBP and DBP) mean values. Treatment with simvastatin reduced SBP to a lesser extent than manidipine.

  Combination therapy with manidipine and simvastatin is either in SBP (−22.7 mmHg, p <0.0001 for placebo) and DBP mean (−18.8 mmHg, p <0.001 for placebo) The drug alone caused a greater drop.

  Simvastatin significantly reduced the total cholesterol (-52.7 mg / dl, p <0.05 vs placebo) mean value. The addition of manidipine did not significantly change the lipid-lowering effect of simvastatin.

  Manidipine alone treatment did not affect plasma PAI-1 activity, but significantly increased t-PA activity (+0.22 U / ml, p <0.05 vs placebo). Simvastatin monotherapy significantly reduced PAI-1 (-8.5 U / ml, p <0.05 vs placebo) and did not significantly affect t-PA activity.

  This combination resulted in a significantly greater decrease in PAI-1 (−8.7 U / ml, p <0.05 vs placebo) and an increase in t-PA activity (+0.24 U / ml, p <0 vs placebo). .05).

  Both manidipine (-17.6 ng / ml, p <0.05 vs placebo) and simvastatin (-30.4 ng / ml, p <0.05 vs placebo) are effective in reducing ICAM-1 levels Met. Interestingly, combination therapy was found to further reduce the ICAM-1 mean value (-47.7 ng / ml, p <0.01 versus placebo).

  Additional effects may also have arisen from the combination treatment for lowering CRP levels, another marker related to the relative risk of developing cardiovascular disease.

  The results obtained suggest that the combination of the present invention may be a useful treatment to reduce risk factors for cardiovascular disease, especially in terms of effects on ICAM-1 and CRP.

Example 2-Effect of manidipine and simvastatin, alone and in combination, in preventing myocardial damage induced by ischemia-reperfusion It was to evaluate the protective effect of the combination.

  The test was performed according to the method described so far (Rossoni G et al Pharmacol Exp Ther. 2003 307 (2), 633-9).

  Male Wistar rats were randomly divided into 6 groups (n = 6-8 rats per group). Manidipine (1 mg / kg and 3 mg / kg) and simvastatin (1 mg / kg) were administered once or daily by oral gavage over 5 consecutive days.

The following parameters were measured:
i) Left ventricular end-diastolic blood pressure (LVEDP) and left ventricular advanced blood pressure (LVDevP, peak left ventricular systolic minus LVEDP),
ii) Activity of creatine kinase (CK) and lactate dehydrogenase (LDH) in cardiac perfusate.

  Data are mean ± SEM E. It was expressed as M (standard deviation of the mean).

  In heart specimens from control animals, ischemia induced a gradual increase in LVEDP after cessation of activity, reaching a peak in about 20 minutes (5 ± 1-37 ± 4 mmHg, P <0.001), even during reperfusion It remained virtually unchanged. In heart specimens from rats treated orally with manidipine, the elevation in LVEDP during ischemia and reperfusion period was significantly reduced depending on the dose used. In contrast, in heart specimens obtained from rats treated with simvastatin (1 mg / kg), the increase in LVEDP values was almost similar to that of rats treated with vehicle. When hearts from rats treated with the combination treatment (manidipine 1 or 3 mg / kg + simvastatin 1 mg / kg) were subjected to ischemia-reperfusion, the value of VEDP was significantly lower than that of the single treatment ( P <0.01), resulting in a corresponding decrease in left ventricular stiffness at the end of reperfusion (FIG. 1). These results are significantly greater than those observed with manidipine alone when statin administered at a dose (1 mg / kg) that is almost ineffective by itself is combined with manidipine (1 or 3 mg / kg). It clearly shows that it has a large and significant anti-ischemic effect. The beneficial effect obtained with the manidipine / simvastatin combination was confirmed by greater contractility recovery and a reduction in CK and LDH in the cardiac perfusate during the reperfusion period. Taken together, these results appear to indicate a synergistic interaction between manidipine and simvastatin in reducing ischemia and ventricular dysfunction during reperfusion.

  The combination of manidipine and statins may therefore be an effective therapy to protect the myocardium from damage associated with postischemic ventricular dysfunction.

FIG. 1 shows the time course of left ventricular end-diastolic blood pressure (LVEDP) in a perfused rat heart specimen subjected to ischemia-reperfusion.

Claims (21)

  (±) -1,4-dihydro-2,6-dimethyl-4- (3-nitro in combination with statins or physiologically acceptable salts for the treatment or prevention of cardiovascular disease Phenyl) -3,5-pyridinedicarboxylic acid 2- [4- (diphenylmethyl) -1-piperazinyl] ethyl methyl ester (manidipine) or a physiologically acceptable salt as a medicament Where the use reduces the risk factor for the cardiovascular disease.   The use according to claim 1, wherein the combination is a defined combination containing manidipine in a defined amount and ratio with the statin.   The combination is a) a therapeutically effective amount of manidipine or a physiologically acceptable salt and pharmaceutically acceptable carrier or diluent thereof in a first unit dosage form, b) a second unit dosage. To contain a therapeutically effective amount of a statin or a physiologically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent in form, and c) the first and second dosage forms The use according to claim 1, which is a kit comprising the container means.   The use according to any one of claims 1 to 3, wherein the risk factor is a complication of hypertension and hyperlipidemia.   Use according to claim 4, wherein the symptom of hyperlipidemia is hypercholesterolemia.   The use according to any one of claims 1 to 3, wherein the risk factor is inflammation and a marker thereof.   Use according to claim 6, wherein the marker of inflammation is intercellular adhesion molecule type-1 (ICAM-1) and / or C-reactive protein (CRP).   The use according to any one of the preceding claims, wherein manidipine is administered in an amount comprised between 5 mg and 30 mg.   Use according to claim 8, wherein the amount of manidipine is comprised between 10 mg and 20 mg.   The statin is selected from lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, pitavastatin, and rosuvastatin selected from the above claims. Use of description.   Use according to claim 10, wherein the statin is simvastatin.   Use according to any one of the preceding claims, wherein the cardiovascular disease is selected from atherosclerosis, coronary artery disease (CAD), myocardial infarction (heart attack), stroke and angina.   Manidipine or physiologically acceptable salt and statin or physiologically in a defined quantity ratio as a defined combination for the manufacture of a pharmaceutical composition for the treatment or prevention of cardiovascular disease Use of acceptable salt. a) Manidipine or a physiologically acceptable salt thereof and a statin or a physiologically acceptable salt thereof in a defined amount and ratio as a defined combination, and b) a pharmaceutically acceptable A pharmaceutical composition comprising a carrier or diluent, wherein the manidipine is in an amount comprised between 5-30 mg and the statin is comprised in an amount comprised between 10-80 mg Composition.   The pharmaceutical composition according to claim 14, wherein manidipine is in the form of hydrochloride.   The pharmaceutical composition according to claim 14 or 15, wherein the statin is simvastatin in an amount comprised between 40 and 80 mg.   The pharmaceutical composition according to any one of claims 14 to 16, wherein the pharmaceutical composition is in a form suitable for oral administration.   18. A pharmaceutical composition according to claim 17, wherein the pharmaceutical composition is in the form of a tablet or capsule.   a) a therapeutically effective amount of manidipine or a physiologically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent in the first unit dosage form, b) in the second unit dosage form. A container means for containing a therapeutically effective amount of a statin or a physiologically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent; and c) the first and second dosage forms. A kit comprising.   20. A kit according to claim 19, wherein the amount of manidipine is comprised between 5 mg and 30 mg.   The kit according to claim 19, wherein the amount of statin is comprised between 2.5 mg and 160 mg.

Images